Biomedical subjects

I-Ching Ho

Publications and source records attributed to I-Ching Ho.

8 recordsLinked to original sources

PubMed2006

Arsenite pretreatment enhances the cytotoxicity of mitomycin C in human cancer cell lines via increased NAD(P)H quinone oxidoreductase 1 expression.

Arsenic is an effective therapeutic agent for the treatment of patients with refractory or relapsed acute promyelocytic leukemia. The use of arsenic for treating solid tumors, particularly in combination with other chemotherapeutic agents, has been extensively studied. Here, we report that arsenite-resistant human lung cancer CL3R15 cells constitutively overexpress NAD(P)H quinone oxidoreductase 1 (NQO1), an enzyme responsible for activation of mitomycin C (MMC), and are more susceptible to MMC cytotoxicity than parental CL3 cells. The effects of arsenite pretreatment on NQO1 induction were examined in CL3, H1299, H460, and MC-T2 cells. Arsenite pretreatment significantly enhanced the expression of NQO1 and susceptibility to MMC in CL3, H1299, and MC-T2 cells, but not in H460 cells that express high endogenous levels of NQO1. Alternatively, arsenic pretreatment reduced adriamycin sensitivity of CL3 cells. Arsenite-mediated MMC susceptibility was abrogated by dicumarol (DIC), an NQO1 inhibitor, indicating that NQO1 is one of the key regulators of arsenite-mediated MMC susceptibility. Various cancer cell lines showed different basal levels of NQO1 activity and a different capacity for NQO1 induction in response to arsenite treatment. However, overall, there was a positive correlation between induced NQO1 activity and MMC susceptibility in cells pretreated with various doses of arsenite. These results suggest that arsenite may increase NQO1 activity and thus enhance the antineoplastic activity of MMC. In addition, our results also showed that inhibition of NQO1 activity by DIC reversed the arsenite resistance of CL3R15 cells.

Antineoplastic Agents↗

PubMed2006

Distinct gene expression profiles in immortalized human urothelial cells exposed to inorganic arsenite and its methylated trivalent metabolites.

Inorganic arsenic is an environmental carcinogen. The generation of toxic trivalent methylated metabolites complicates the study of arsenic-mediated carcinogenesis. This study systematically evaluated the effect of chronic treatment with sodium arsenite (iAs(III)), monomethylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)) on immortalized human uroepithelial cells (SV-HUC-1 cells) using cDNA microarray. After exposure for 25 passages to iAs(III) (0.5 microM), MMA(III) (0.05, 0.1, or 0.2 microM), or DMA(III) (0.2 or 0.5 microM), significant compound-specific morphologic changes were observed. A set of 114 genes (5.7% of the examined genes) was differentially expressed in one or more sets of arsenical-treated cells compared with untreated controls. Expression analysis showed that exposure of cells to DMA(III) resulted in a gene profile different from that in cells exposed to iAs(III) or MMA(III), and that the iAs(III)-induced gene profile was closest to that in the tumorigenic HUC-1-derived 3-methylcholanthrene-induced tumorigenic cell line MC-SV-HUC T2, which was derived from SV-HUC-1 cells by methylcholanthrene treatment. Of the genes affected by all three arsenicals, only one, that coding for interleukin-1 receptor, type II, showed enhanced expression, a finding confirmed by the reduced increase in NF-kappaB (nuclear factor kappa B) activity seen in response to interleukin-1beta in iAs(III)-exposed cells. The expression of 11 genes was suppressed by all three arsenicals. 5-Aza-deoxycytidine partially restored the transcription of several suppressed genes, showing that epigenetic DNA methylation was probably involved in arsenical-induced gene repression. Our data demonstrate that chronic exposure to iAs(III), MMA(III), or DMA(III) has different epigenetic effects on urothelial cells and represses NF-kappaB activity.

Arsenites↗

PubMed2005

Oxidative stress mediates sodium arsenite-induced expression of heme oxygenase-1, monocyte chemoattractant protein-1, and interleukin-6 in vascular smooth muscle cells.

Arsenic exposure is associated with an increased risk of vascular disorders, and results in increased oxidative stress in endothelial cells and vascular smooth muscle cells (VSMCs). Since oxidative stress is involved in regulating the expression of genes related to atherogenesis, we investigated its involvement in the enhanced expression of three atherosclerosis-related genes coding for heme oxygenase-1 (HO-1), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in VSMCs treated with inorganic sodium arsenite (iAs). In human VSMCs (hVSMCs) and rat VSMCs (rVSMCs), HO-1, MCP-1, and IL-6 mRNA levels were significantly increased by iAs treatment. An increase in HO-1 protein levels in hVSMCs was confirmed by Western blotting technique, while increased MCP-1 and IL-6 secretion by hVSMCs was demonstrated by enzyme-linked immunosorbent assay. Although modulators of oxidative stress inhibited this iAs-induced increase in the expression of these three genes, different modulators had differential effects. In iAs-treated rVSMCs, catalase, dimethylsulfoxide, and L-omega-nitro-L-arginine significantly inhibited the increase in expression of all three genes, allopurinol inhibited the increase in MCP-1 and IL-6 expression, but had no effect on HO-1 expression, while superoxide dismutase had no significant effect on HO-1 expression, but had an inhibitory effect on IL-6 expression and a stimulatory effect on MCP-1 expression. Therefore, iAs may enhance the expression of HO-1, MCP-1, and IL-6 in VSMCs via different reactive oxygen molecules. Furthermore, using tin protoporphyrin IX (SnPP) and anti-MCP-1 antibody to abolish iAs-induced HO-1 and MCP-1 activity, respectively, shows that HO-1 has protective effect against iAs-induced injury in VSMCs and MCP-1 is chemoattractive to human monocytes, THP-1.

Animals↗

PubMed2004

Multi-class clustering and prediction in the analysis of microarray data.

DNA microarray technology provides tools for studying the expression profiles of a large number of distinct genes simultaneously. This technology has been applied to sample clustering and sample prediction. Because of a large number of genes measured, many of the genes in the original data set are irrelevant to the analysis. Selection of discriminatory genes is critical to the accuracy of clustering and prediction. This paper considers statistical significance testing approach to selecting discriminatory gene sets for multi-class clustering and prediction of experimental samples. A toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV with a total of 55 samples) is used to illustrate a general framework of the approach. Among four selected gene sets, a gene set omega(I) formed by the intersection of the F-test and the set of the union of one-versus-all t-tests performs the best in terms of clustering as well as prediction. Hierarchical and two modified partition (k-means) methods all show that the set omega(I) is able to group the 55 samples into seven clusters reasonably well, in which the As and AsV samples are considered as one cluster (the same group) as are the Cd and Cu samples. With respect to prediction, the overall accuracy for the gene set omega(I) using the nearest neighbors algorithm to predict 55 samples into one of the nine treatments is 85%.

Algorithms↗

PubMed2004

Gene selection for sample classifications in microarray experiments.

DNA microarray technology provides useful tools for profiling global gene expression patterns in different cell/tissue samples. One major challenge is the large number of genes relative to the number of samples. The use of all genes can suppress or reduce the performance of a classification rule due to the noise of nondiscriminatory genes. Selection of an optimal subset from the original gene set becomes an important prestep in sample classification. In this study, we propose a family-wise error (FWE) rate approach to selection of discriminatory genes for two-sample or multiple-sample classification. The FWE approach controls the probability of the number of one or more false positives at a prespecified level. A public colon cancer data set is used to evaluate the performance of the proposed approach for the two classification methods: k nearest neighbors (k-NN) and support vector machine (SVM). The selected gene sets from the proposed procedure appears to perform better than or comparable to several results reported in the literature using the univariate analysis without performing multivariate search. In addition, we apply the FWE approach to a toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV) for a total of 55 samples for a multisample classification. Two gene sets are considered: the gene set omegaF formed by the ANOVA F-test, and a gene set omegaT formed by the union of one-versus-all t-tests. The predicted accuracies are evaluated using the internal and external crossvalidation. Using the SVM classification, the overall accuracies to predict 55 samples into one of the nine treatments are above 80% for internal crossvalidation. OmegaF has slightly higher accuracy rates than omegaT. The overall predicted accuracies are above 70% for the external crossvalidation; the two gene sets omegaT and omegaF performed equally well.

Colonic Neoplasms↗

PubMed2004

Association of chromosomal alterations with arsenite-induced tumorigenicity of human HaCaT keratinocytes in nude mice.

Inorganic arsenic is a well-documented human carcinogen. Chronic low-dose exposure to inorganic arsenic is associated with an increased incidence of a variety of cancers, including skin, lung, bladder, and liver cancer. Because genetic alterations often occur during cancer development, the objective of this study was to explore what types of genetic alterations were induced by chronic exposure of human HaCaT cells to arsenic. After 20 passages in the presence of inorganic trivalent arsenite at concentrations of 0.5 or 1 microM, HaCaT cells had higher intracellular levels of glutathione, became more resistance to arsenite, and showed an increased frequency of micronuclei. Furthermore, the previously nontumorigenic HaCaT cells became tumorigenic, as shown by subcutaneous injection into Balb/c nude mice. Cell lines derived from the tumors formed by injection of arsenite-exposed HaCaT cells into nude mice expressed higher levels of keratin 6, a proliferation marker of keratinocytes, than did parental HaCaT cells, whereas the expression of keratins 5, 8, and 10 was significantly decreased. Comparative genomic hybridization demonstrated chromosomal alterations in the 11 cell lines derived from these tumors; all 11 showed significant loss of chromosome 9q, and seven showed significant gain of chromosome 4q. The present results show that long-term exposure to low doses of arsenite transformed nontumorigenic human keratinocytes to cells that were tumorigenic in nude mice and that chromosomal alterations were observed in all cell lines established from the tumors.

Animals↗

PubMed2003

Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects.

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0-4.32 microg/L), intermediate (4.64-9.00 microg/L), and high (9.60-46.5 microg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncogene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagenase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease.

Arsenic↗

PubMed2002

Arsenite pretreatment attenuates benzo[a]pyrene cytotoxicity in a human lung adenocarcinoma cell line by decreasing cyclooxygenase-2 levels.

Both simultaneous and sequential exposure to arsenite and benzo[a]pyrene (BaP) potentially occur in human populations drinking arsenic-contaminated water or burning arsenic-contaminated coal. Although arsenite and BaP are both well-documented hazardous substances and human carcinogens, interactions between these two agents have not been well defined. In this study, we demonstrated that posttreatment with arsenite synergistically enhanced the cytotoxicity of BaP for a human lung adenocarcinoma cell line, CL3. In contrast, pretreatment of CL3 cells with arsenite attenuated BaP cytotoxicity. Involvement of heat-shock protein 70 and heme oxygenase-1 in this arsenite-mediated attenuation of BaP cytotoxicity was ruled out. Our data also indicated that arsenite pretreatment did not affect the BaP-mediated induction of CYP1A1, the initial enzyme involved in its metabolic activation, but did result in a significant decrease in mRNA and protein levels of cyclooxygenase-2 (COX-2), which is required to convert the BaP metabolite BaP 7,8-dihydrodiol to the ultimate epoxide. In contrast to the high susceptibility of CL3 cells to BaP, the human lung carcinoma cells, H460, and CL3R15 cells (arsenic-resistant CL3 cells) showed normal CYP1A1 inducibility by BaP, had negligible amounts of COX-2, and were highly resistant to BaP. The involvement of COX-2 in BaP activation was confirmed by transfection of H460 cells with a recombinant adenovirus, Ad-pgk-Cox2, coding for COX-2, which resulted in a significant increase in the levels of the COX-2 product prostaglandin E2 in the medium and in the susceptibility of H460 cells to BaP. The present study confirms the importance of COX-2 in BaP activation and demonstrates that the arsenite-mediated attenuation of BaP cytotoxicity is mediated by a reduction in COX-2 levels.

Adenocarcinoma↗